Multi-layered tablets that provide different release profiles for one or more different drugs are known.
U.S. Pat. No. 4,999,226 to Schock et al. discloses a multi-layered tablet having two different drug-containing layers separated by a layer comprising a pharmaceutically inert excipient. The inert layer provides a barrier layer between the drugs layers, in order to solve the problems associated with the physical and chemical incompatibilities between the drugs.
U.S. Pat. No. 5,342,627 to Glaxo Canada Inc. discloses a device for the release of at least one active substance into a fluid medium by dissolution comprising a covering, which is impermeable to the active substance and the fluid, or is swellable or slowly soluble in said fluid, having at least one aperture therein and defining a shaped cavity, the cavity being filled by a shaped core comprising the active substance. The covering composition is compressed onto a pre-shaped core of active substance. The geometric configuration of the compression-coated core controls the release profile of drugs. The device may be provided with an outer soluble coating which provides an initial delay before release of active substance begins, or alternatively provides an immediate dose of active substance.
The U.S. Pregrant Patent Application Publication No. 20020128251 to GlaxoSmithKline discloses a layered tablet formulation comprising an immediate release layer and a slow release layer. The layered tablet may have two layers, or two layers plus one or more barrier layer, as well as a coating layer. The coating layer may itself contain active material content, and may, for example, be an immediate release layer, which immediately disintegrates in contact with water or aqueous media to release its active material content.
U.S. Pregrant Patent Application Publication No. 20040115265 to Bristol Meyers Squibb discloses a multi-layered tablet that includes two drug-containing layers separated by a middle barrier layer to minimize interaction of the drugs.
U.S. Pat. No. 6,660,299 to Beecham Pharmaceuticals Limited discloses a multi-layered tablet consisting of a slow release layer, a rapid release layer and optionally a barrier layer, which may be located between the respective first and second layers, and/or on one or more of the outer surfaces of the first and second layers, for example the end faces of the layers of a substantially cylindrical tablet. The tablet consisting of an immediate release and a slow release layer can be optionally coated with a coating layer. The barrier layer is designed to retain sufficient physical integrity at least until complete or substantially complete release of drug.
SCOLR Pharma, Inc. (Bellevue, Wash.) has filed an application with the United States Patent Office on an Asymmetrical Multiple Layered Tablet for Controlled Release. The technology is reportedly designed to work with single or multiple ingredients and/or drugs, allowing those ingredients/drugs to be programmed for release at pre-selected rates and/or at pre-selected regions within the body.
SkyPharma offers the GEOMATRIX™ combination tablet, which is a bimodal release multi-layered tablet made by compression. The GEOMATRIX™ tablet comprises two opposing barrier layers that module release of drug from a middle layer to provide controlled release of drug from the middle layer (Conte et al., Pharm. Technol. 22, No. 3, 174-82, 1998). This technology is further described in U.S. Pat. No. 4,839,177 to Jagotec AG.
U.S. Pat. No. 5,738,874, U.S. Pat. No. 6,183,778, and U.S. Pat. No. 6,294,200 to Jagotec AG disclose multi-layered tablet formulations.
The SMARTRIX™ combination tablet (www.smartrix.com) is a bimodal release multi-layered tablet having a controlled release drug-containing layer, containing a first drug, placed between two stacked rapidly eroding layers, either one or both of which contains a different second drug. The middle layer has a biconcave surface whereas the upper and lower layers have a convex layer that mates with the middle layer and an outer flat surface. The shape of the surface(s) between the layers can be varied to provide specific drug release profiles from the core.
PCT International Publication No. WO 03/105809 discloses a two-layered tablet containing pioglitazone in immediate release form and metformin in prolonged release form.
PCT International Publication No. WO 03/101431, U.S. Pregrant Patent Application Publication No. 20030092724, and U.S. Pat. No. 6,372,255 disclose a bi-layered tablet having an immediate release layer and a controlled release layer.
Japanese Patent Application No. 1989-287048, French Patent Application No. 1999-0000625, U.S. Pat. No. 5,637,320, and Omori at al. (Pharm. Tech. Jpn, 2001, 17(9), pp. 1429-1432, 1435-1441) disclose layered formulations that provide an immediate and slow release of drug.
European Patent Application EP 1260216 discloses a concentrically bi-layered tablet comprising a first portion having at least one discrete outer layer comprising a therapeutically effective amount of at least one pharmaceutically active ingredient capable of intraoral administration, and a second portion located within said first portion that comprises a therapeutically effective amount of at least one pharmaceutically active ingredient capable of oral administration and which is releasable and orally ingestible by the patient after the outer layer has disintegrated or has dissolved intraorally. The second portion can provide immediate release or sustained release of the pharmaceutically active ingredient.
Japanese Patent Application No. 1996-211279 discloses a multi-layered tablet having a variety of different layers.
U.S. Pregrant Patent Application Publications No. 20040253311 and No. 20040186184 disclose a multi-layered tablet having a combination of a decongestant and an anti-histamine.
PCT International Publication No. WO 04/064815 discloses a three-layered tablet having an immediate release layer of famotidine, an immediate release layer of aspirin and a slow release layer of famotidine.
U.S. Pat. No. 5,093,200 discloses a multi-layered tablet having a rapid release layer, a slow release layer and metal stearate layer between the other two layers.
U.S. Pat. No. 5,681,583 discloses a multi-layered tablet having a variety of different layers for rapid, controlled and gradual release.
U.S. Pat. No. 5,395,626 and U.S. Pat. No. 5,474,786 discloses multi-layered particles that comprise concentric coatings to provide immediate and sustained release of drug.
U.S. Pat. No. 5,968,554 to Beiman et al. discloses a delivery system that contains a core comprising an active pharmaceutical, an enteral coating over the core comprising a pH dependent water soluble polymer, a second coating of the active pharmaceutical, and thereafter a coating that is soluble in gastric juices.
U.S. Pat. No. 5,162,117 to Schering Corporation describes a two pulse tablet of flutamide designed to provide an immediate release dose and a second delayed dose in pulsatile manner in the gastrointestinal tract. The first pulse is contained in an immediate release layer while the second pulse is obtained from a core which contains a solid dispersion of the flutamide in a carrier. The pulses are separated by a film layer of an enteric coating at 4-15% weight percent of the core.
U.S. Pat. Nos. 6,238,699 and 6,756,056 disclose an oral antiparkinson drug delivery system consisting of carbidopa and levodopa in immediate and sustained release compartments. An outer layer comprising an immediate release composition comprising carbidopa and levodopa is separated by an intermediate excipient layer from a core layer comprising a sustained release composition comprising carbidopa and levodopa.
Other patents disclosing a controlled release dose form containing levodopa and carbidopa which requires immediate release and controlled release components include U.S. Pregrant Patent Application Publications No. 20030224045, No. 20030228360, No. 20030031707, and No. 20040166159, and the PCT International Publication No. WO 00/15197.
Multi-layered osmotic devices that provide a controlled release of drug from a core and a rapid/immediate release of drug from an external coating are known. U.S. Pat. No. 6,004,582, U.S. Pat. No. 6,521,255, U.S. Pat. No. 6,569,456, U.S. Pat. No. 6,572,890, U.S. Pat. No. 6,599,532, U.S. Pat. No. 6,605,302, U.S. Pat. No. 6,613,357, and the PCT International Publications No. WO04/056335 and No. WO04/087095 to Osmotica Corp. disclose various embodiments of a multi-layered osmotic device, wherein an osmotic core is surrounded by an immediate or rapid release drug-containing composition.
Thombre et al. (J. Controlled Release 94(1), 75-89, 2004) disclose an osmotic device having a monolithic, bi-layered or tri-layered core.
U.S. Pat. No. 4,576,604 to Alza Corporation discloses several different embodiments of an osmotic device having a drug in the core and at least one lamina surrounding the core.
U.S. Pat. No. 4,801,461 to Alza Corporation discloses an osmotic dosage form comprising pseudoephedrine in the core, a semipermeable wall surrounding the core comprising varying amounts of cellulose acetate or cellulose triacetate and varying amounts of hydroxypropylcellulose, a passageway in the wall for delivering the drug from the core and, optionally, a lamina on the outside of the wall comprising pseudoephedrine.
U.S. Pat. No. 4,810,502 to Alza Corporation discloses an osmotic dosage form for delivering pseudoephedrine (Ps) and brompheniramine (Br) which comprises a core containing Ps and Br, a wall surrounding the core comprising cellulose acylate and hydroxypropylcellulose, a passageway in the wall for delivering the drug, and a lamina on the outside of the wall comprising Ps, BR, at least one of hydroxypropylcellulose or hydroxypropyl methylcellulose, and poly(ethylene oxide) for enhancing the mechanical integrity and pharmacokinetics of the wall.
U.S. Pat. No. 5,057,321, and U.S. Pat. No. 5,128,145 to Alza Corporation disclose a dosage form comprising a wall surrounding a compartment, the wall comprising at least in part a semipermeable polymeric composition permeable to the passage of fluid and substantially impermeable to the passage of drug, a layer in the compartment comprising a formulation comprising a dosage unit amount of a drug for performing a therapeutic program and a maltodextrin, a layer in the compartment comprising an osmotic formulation for imbibing, and absorbing fluid for expanding in size for pushing the drug maltodextrin formulation from the dosage form, and at least one passageway in the wall for releasing the drug. In one embodiment an immediate release lamina is compressed or air sprayed around the external surface of the delivery device to yield an immediate release coat.
U.S. Pat. No. 5,190,763, U.S. Pat. No. 5,192,550, U.S. Pat. No. 5,221,536 and U.S. Pat. No. 6,217,905 to Alza Corporation disclose a dosage form comprising: a wall surrounding a compartment, the wall comprising at least in part a semipermeable polymeric composition permeable to the passage of fluid and substantially impermeable to the passage of an anti-Parkinson drug; a layer in the compartment comprising a formulation comprising a dosage unit amount of an anti-Parkinson drug for performing a therapeutic program; a layer in the compartment comprising an osmotic formulation for imbibing and absorbing fluid for pushing the anti-Parkinson formulation from the dosage form; and, at least one passageway in the wall for releasing the anti-Parkinson drug. In one embodiment an immediate release lamina is compressed or air sprayed around the external surface of the delivery device to yield an immediate release coat.
U.S. Pat. No. 5,558,879 to Andrx Pharmaceuticals discloses a controlled release tablet for water soluble drugs in which a passageway is formed in the environment of use, i.e., the GI tract of a person receiving the formulation. The controlled release tablet consists of a core, a dual layer membrane coating around the core, and an outer immediate release coating containing a drug and a water soluble polymer.
U.S. Pat. No. 5,681,584 to Alza Corporation discloses a controlled release drug delivery device comprising a core containing a drug, an optional osmotic agent and optional excipients, a delayed release jacket comprising at least one of a binder, an osmotic agent and a lubricant surrounding the core, a semipermeable membrane surrounding the delayed release jacket and optionally having a passageway, a drug containing layer either on the outside of the semipermeable membrane or between the semipermeable membrane and the delayed release jacket, and an optional enteric coat either on the outside of the drug-containing layer, between the drug-containing layer and the semipermeable membrane or on the outside of the semipermeable membrane when the drug-containing layer is between the delayed release jacket and the semipermeable membrane.
U.S. Pregrant Patent Application Publication No. 20050025831 to Alza Corporation discloses an osmotic dosage form comprising a longitudinally compressed tablet core containing a plurality of layers wherein a drug is contained in at least one layer and at least one other layer comprises a suitable fluid-expandable polymer, a semipermeable wall surrounding said longitudinally compressed tablet core to thereby form a compartment having an osmotic gradient to drive fluid from an external fluid environment contacting said semipermeable wall into said compartment, and an orifice formed through said semipermeable wall and into said longitudinally compressed tablet core to permit drug to be released from within said compartment into said external fluid environment. The dosage forms may additionally comprise an immediate-release dose of drug.
U.S. Pat. No. 6,544,554 to Chugai Seiyaku Kabushiki Kaisha discloses a formulation that has a drug core surrounded by a release control layer to present a mechanism by which the drug in the core is rapidly released after a predetermined delay in time. The formulation also has a rapid drug release portion provided outside the release control layer so that the drug can be released more than once at intervals after single dosing. Further in addition, the invention relates to a formulation that incorporates a plurality of drugs in both a core and one or more drug release layers so that different active ingredients can be released at different times.
While the prior art discloses a wide variety of oral multi-layered tablets, none of the prior art discloses a multi-layered tablet for a triple combination release of active agents to an environment of use. Thus, there is a need for a drug delivery system that provides a triple combination release of at least one active agent. Such a system could improve patient compliance to a drug regimen or offer opportunities of treatment otherwise not attainable.